The effect of various metals on biological processes has generally been referred to as an xe2x80x9coligodynamicxe2x80x9d action. A detailed discussion of the history of such oligodynamic action with particular emphasis on the use of silver is contained in Chapters 24 and 28 of the monograph by Lawrence and Block, Disinfection, Sterilization, and Preservation, Lea and Febiger, Philadelphia, 1968. Consequently, Chapters 24 and 28 of Lawrence and Block""s treatise on disinfection are cited herein by reference in their entirety.
Goodman and Gilman (1943) reported that the toxic effects of silver compounds on microorganisms is probably due to the silver ions which precipitate the protein of bacterial protoplasm. It is very well known that soluble silver salts such as silver nitrate will quickly precipitate protein and oxidize to a dark brown or black precipitate. The silver protein complex so formed contributes to a sustained antiseptic action by slowly liberating small amounts of silver ions. Goodman and Gilman felt it probable that in the use of simple salts of silver as antiseptics, some metallic silver is obtained by reduction and that its oligodynamic action contributes to the anti-bacterial effect.
Studies examining the mechanism of action by silver in demonstrating antimicrobial activity led various workers to conclude that the surface area of silver ions was more important that the amount of silver nor the time that the substrate containing microbes was exposed to the silver. The silver was prepared in the form of a spongy metallic form or by coating various products which contain large surfaces such as sand. Thus Sxc3xcpfle and Werner (1951) were able to show that E. coli placed in flasks having counts of 18,000 E. coli per ml of water. When such counts were exposed to flasks containing sand coated with silver at a concentration of 10% silver of the amount of sand, would result in a sterile environment in four hours. Even counts as high as 120,000 E. coli per ml of solution, resulted in sterility in 24 hours.
Clinical studies utilized a silver powder prepared by Rochat and Uzdins (1947) showed that particles of silver of a size of 2 microns to {fraction (1/100)} of a micron, when prepared in the form of a paste could be used to treat dental root canals, in the form of a spray to treat tonsillitis, or in the form of a powder in water suspension to treat abrasions and burns. Such silver compounds were successful for the treatment of severe burns, carbuncles and infected wounds. As such, the silver preparations promoted tissue granulation, suppressed fecal odors of wounds, accelerated healing, as well as prevented keloid formulation.
Kreidl and Kreidl (U.S. Pat. No. 2,396,514) prepared a cloth or gauze by treating the material with a solution of a silver compound, such as silver nitrate, followed by a soluble halide such as sodium chloride and after a period of time, which resulted in an insoluble silver chloride precipitate being impregnated into the cloth, they washed off the excess of silver chloride that was not absorbed onto the material, so resulting in an impregnated material which had antiseptic properties. The dressing containing silver chloride as prepared by Kreidl and Kreidl would have exerted minimal antimicrobial activity because, as is well-known in the profession, silver chloride is a highly insoluble chemical and is insoluble in water or other aqueous solutions to the extent of 0.00008910 parts per 100 ml of water.
Schwartz (U.S. Pat. No. 2,459,896) impregnated fibers such as nylon fibers with colloidal silver and then reduced the silver by treating the preparation with alkylamines. These fibers were then shown to have antimicrobial activity. Here also in the Schwartz patent nylon fibers which are not soluble in aqueous solutions or tissue exudate, would be expected to have very low antimicrobial activity, because the only colloidal silver that would be available to act on microorganisms are those colloidal silver particles on the very surface of the nylon fiber and they would essentially be few and far between and fixed in situ of the nylon. In addition, such a preparation of a colloidal silver-impregnated nylon fiber would not have the characteristics that have been shown to be important in utilizing silver as an antimicrobial agent, in that the total silver surface area of silver ions available to the tissue exudate would be minimal, because colloidal silver is silver in the non-ionic state.
In a subsequent patent (U.S. Pat. No. 2,459,897) Schwartz also produced fibers that were impregnated with silver and reducing agents of silver in which the reduction of the silver was achieved with heterocyclic secondary amines such as piperidine or pyrrolidine. These fibers thereby developed antimicrobial activity. In this patent of Schwartz (U.S. Pat. No. 2,459,897), Schwartz recognized the necessity to reduce the free silver to silver ions and thereby incorporated secondary amines which acted as reducing agents which were also impregnated into the nylon fibers in order to procure antimicrobial activity. Here also, however, the only antimicrobial activity that would be available to a tissue exudate would be those on the very surface of the fiber and all of the reduced silver ions present inside the nylon fiber would not be available to the tissue exudate, therefore, the antimicrobial activity would be diminished.
Goetz, in his U.S. Pat. No. 2,521,713 formed silver complexes which were antimicrobial by utilizing a finely divided silver oxide sludge and finely divided zinc oxide to react for a short period of time. The mixture was then dried and made into granules or pellets. These complexes in the form of a paste could be used as germicides for the treatment of burns, wounds, or skin infections. In this patent by Goetz, the silver oxide sludge so prepared would be expected to have minimal antimicrobial activity, because silver oxide in the form of Ag2O is soluble in aqueous solutions (and therefore tissue exudates) to the extent of 0.001320 parts per hundred. The oxide of silver as silver oxide Ag2O is essentially considered insoluble in water. Because of the highly insoluble nature of the silver oxides, ionization of the silver oxides would be minimal and therefore antimicrobial activity also would be significantly diminished.
In a patent by Wilhelm Dieck and Sally Schiff (U.S. Pat. No. 2,008,131) the inventors relied exclusively on oxides of silver to procure antimicrobial activity. Thus even when a solution of silver permanganate utilized by the inventors was reduced, the inventors indicate the possible production of a silver oxide-manganite compound, which compound may (emphasis added) be a silver manganite compound having the composition of Ag2O2MnO2.
Consequently, the remarks we have made above stipulating the high degree of insolubility of the silver oxide compounds are germane to the Dieck and Schiff patent. Further, even if the hypothetical compound, such as the silver manganite formula postulated by the authors was correct, there are no experiments cited to determine whether any antimicrobial activity is due to the highly insoluble silver oxides or to the presumed manganese oxide which the authors set forth in a number of the claims of their invention.
In the patent by Conconi (U.S. Pat. No. 2,283,883) the inventor claims that pure silver, when impregnated into a clay or related porous candle, will act as a filter to inactivate microorganisms present in solutions that are passed through such a filter. The invention of Conconi claims that the oligodynamic effect is highest when the metallic agent consists of pure silver. However, Conconi prepares his presumable silver clay matrix in the form of a candle by starting with silver nitrate and then reducing the silver nitrate with reducing agents to form metallic silver. Nowhere in Conconi""s invention is it shown that 100% of the silver nitrate has been so reduced to metallic silver since even very dilute solutions of silver nitrate are well known in the profession to be highly antimicrobial in their activity and even trace amounts of silver nitrate that have not been reduced would show very marked antimicrobial activity. In any event, the patent of Conconi in all of the claims relies exclusively on pure silver in the form of a silver ceramic or clay candle to act as an antibacterial agent for solutions that would be passed through such a candle.
The present specification refers to the following publications all of which are incorporated herein by reference.
Goodman, L. and Gilman, A., 1065 The Pharmacological Basis of Therapeutics, 3rd Ed. New York, The Macmillan Company.
Lawrence, C. A. and Black, S. S., Disinfection, Sterilization and Preservation, Lea and Febiger, Phil., 1968, Chapters 24 and 28.
Rochat, C. and Uzdins, K., 1947 Katadyn (silver preparation): clinical application. Schweiz med. Wochschr., 77, 1100-1104.
Sxc3xcpfle, K. and Werner, R., 1951 Microdeosimetric investigation of the oligodynamic effect of silver. Mikrochemie ver Mikrochim. Acta., 36/47, 866-881.
The rationale I have discovered in preparing a silver alginate molecule as an antimicrobial agent for use in dressing has to do with the fact that soluble silver salts, such as silver nitrate, react with alginates, such as sodium alginate to form an aqueous-insoluble silver alginate moiety. The silver alginate will slowly soften in tissue exudate and gradually begin to dissolve, slowly releasing silver ions. In addition, a small amount of colloidal silver present in the dressing has the advantage of being molecular silver, whose gradual reduction over an extended period of time will release silver ions which have excellent oligodynamic activity.
In addition to the silver alginate as a component of the medical dressing which I have designed, an additional amount of calcium alginate may be present in the dressing as well as colloidal silver. Both have attributes which enhance the efficacy of the antimicrobial activity of the dressing. Thus, I find that an amount of calcium alginate present together with the silver alginate in the dressing acts to retain the integrity of the gel structure of the dressing that is to be applied to a wound or burn when the silver alginate begins to release silver ions, thereby softening the matrix in which the silver alginate is contained if calcium alginate were not present, This is due to the fact that calcium alginate forms a more stable and stronger molecular structure that silver alginate due to the very strong binding between the calcium ions and the alginate molecule. A concentration as little as one part in 100,000 of sodium alginate in aqueous solution can result in precipitation of calcium alginate in the presence of such calcium salts as calcium chloride. Consequently the use of silver alginate in a matrix of calcium alginate retains a stronger integrity of the dressing when applied to a wound over an extended period of time.
There are polymers other than calcium alginate, which can form a high viscosity matrix to be mixed with the silver alginate. Such polymers include Sodium Carboxymethylcellulose, Xanthan Gum, Hyaluronic Acid, Polylactic Acids, Pectin, Natural Gums, (like Acacia, Agaragar, Karaya, Tragacanth, Locust, Guar, Xanthan, Gelan Gum), Cellulose Gums (like Carboxymethylcellulose, Methylcellulose, Hydroxypropyl, Hydroxyethylcellulose) etc.
The release of silver ions from the silver alginate acts to immediately provide an oligodynamic antimicrobial action. The presence of colloidal silver, which will slowly reduce over an extended period of time, will act to prolong the antimicrobial activity of the silver ions, because of the gradual reduction of the colloidal silver to silver ions. It is well accepted that colloidal preparations of silver are actually very finely divided particles of silver, which are so small that they appear to go into solution, but are actually permanent suspensions of insoluble silver.
My composition of silver alginate to be incorporated into medical or veterinary dressings for the treatment of wounds or burns, acquires an additional attribute which is desirable in maintaining the antimicrobial activity of silver in a medical dressing as opposed to other silver compounds currently in use. Thus for example, silver sulphadiazine has been used as a component for medical dressings for use in the treatment of wounds, lesions, ulcers, and burns and this compound is a complex in which silver has been covalently linked to the sulfonamide, sulphadiazine (U.S. Pat. Nos. 6,153,215; 5,989,535). The mechanism of action of the sulfonamides stems from the fact that they are essential metabolic inhibitors of para-aminobenzoic acid (PABA). The antimicrobial action of the sulfonamides is due to the circumstance that PABA, which is part of the folic acid molecule, is essential to many microorganisms, but is not essential to mammalian cells. Mammals do not have to synthesize folic acid, but absorb it from their diet. The related sulfonamides to the sulphadiazine in silver sulphadiazine such as sulfamerazine, sulphanilamid, and many others, requires that a sulfonamide that will act as an antagonist to PABA must have a primary aromatic amino group and this amino group must not be substituted unless by a group which is readily broken down in the body. This means that microorganisms that become resistant to sulphadiazine will also be resistant to a wide series of other sulfonamides that have the primary aromatic amino group. Because of the possible risk in establishing a family of resistant organisms that otherwise would be susceptible to sulfonamides, I have chosen to covalently link the silver molecule to alginate which has no nitrogen and is essentially innocuous as a sensitizing agent or as a potential to result in the selection of microorganisms resistant to sulfonamides that otherwise would remain susceptible.
The use of various dressings frequently require that they be very soft and amendable to being draped around fingers, arm, or legs where injury has occurred. Consequently, it is a desirable attribute of such dressings to be highly flexible and amenable to being easily draped without their surface being distorted by the stress of such draping. It has been discovered that the addition of a compound such as sodium tetraborate (borax) results in the silver alginate foam composition to become highly flexible, have an increased elasticity, and can be readily draped around small circumferences such as a finger without distortion or breakage of the alginate dressing so formed.
Since the silver alginate foam composition prepared herein is highly viscous and would result in a viscosity that may be difficult to layer in a homogeneous thin layer on a plate to permit its drying, it was discovered that the addition of ammonia in aqueous solution or ammonium salts would reduce the viscosity of the silver alginate foam composition and significantly improve the ease with which the layering of the silver alginate foam composition may be layered. Since, during the drying process, free ammonia is liberated from such a composition, which has included the use of a solution of ammonia, liberation of the ammonia will then result in enhanced viscosity and concomitantly increase strengthening of the foam composition thus prepared by the removal of ammonia during the drying process.
Having set forth the tenets of the invention contained herein the following non-limiting examples illustrate various compositions that are inherent in our invention.